Alterations in the Natural Killer (NK) cell system in healthy humans will be investigated in a comprehensive cross-sectional study with special reference to aging. In view of the elevated incidence of neoplasia in the elderly, it is important to learn about the NK cell biology in healthy aged humans. Studies by others on this subject have been very limited, performed on impure cell preparations employing a single, conventional semi-quantitative assay and yielded conflicting results. The multi-technique approach used in our preliminary studies have revealed that the healthy elderly (greater than 80 yr) represent a homogeneous group, expressing an average peripheral blood NK cell activity higher than that of younger adults (20-40 yr). We propose to investigate the alterations in the NK cell frequency and expression by performing cytolytic funtional assays, kinetic analysis of tumor target lysis, surface phenotype (N-901, Leu-7 and Leu-11a) determination, differential sensitivity to ATP (a negative modulator of NK activity), and interferon as well as and an assessment of the critical steps in NK cytolysis (target binding, frequency of active NK cells and recycling capacity) by using a single-cell assay on semi-solid matrix. Highly enriched large granular lymphocytes from 300 healthy volunteers (20-100 yrs) will be utilized. Correlations will be sought between the NK cell surface marker expression and many of the cytolytic steps that may distinguish the individuals in the intra- and inter-age groups. Influence of age on the NK cell recycling capacity and its interacting ability with tumor targets will be examined. We will also examine the cause(s) for an elevated maximal cytotoxic potential (Vmax) exhibited by the elderly (greater than 80 yr). We will determine if the NK activity per cell or NK cell frequency goes up with age. Furthermore, based on a proposition that the higher level of NK activity in the greater than 80 yr old humans may be attributable to a deletion of a population of younger individuals with lower NK activity, a late-life (greater than 70 yr) longitudinal study will be initiated. Accomplishment of these objectives might reveal if the critical cytolytic steps that distinguish the low and high NK activity of young adults are the same that separate the younger from the elderly NK cell features, helping to elucidate age-associated modulations. It is also hoped that the results might form a basis for future pharmacological interventions.